Catecholamines play a central role in the regulation of energy expenditure, in part by stimulating lipid mobilization through lipolysis in fat cells. The beta-2 adrenoceptor (BAR-2) is a major lipolytic receptor in human fat cells. To determine whether known polymorphisms in codons 16, 27, and 164 of this receptor play a role in obesity and subcutaneous adipocyte BAR-2 lipolytic function, we investigated a group of 140 women with a large variation in body fat mass. Only the polymorphisms in codons 16 and 27 were common in the study population. The Gln27Glu polymorphism was markedly associated with obesity with a relative risk for obesity of approximately 7 and an odds ratio of approximately 10. Homozygotes for Glu27 had an average fat mass excess of 20 kg and approximately 50% larger fat cells than controls. However, no significant association with changes in BAR-2 function was observed. The Arg16Gly polymorphism was associated with altered BAR-2 function with Gly16 carriers showing a fivefold increased agonist sensitivity and without any change in BAR-2 expression. However, it was not significantly linked with obesity. These findings suggest that genetic variability in the human BAR-2 gene could be of major importance for obesity, energy expenditure, and lipolytic BAR-2 function in adipose tissue, at least in women.
Abstract. Hellstro Èm L, Wahrenberg H, Hruska K, Wahrenberg H, Reynisdottir S, Arner P (Danderyd Hospital and Karolinska Institute, Stockholm, Sweden). Mechanisms behind gender differences in circulating leptin levels. J Intern Med 2000; 247: 457±462.Objectives. To investigate gender differences in circulating leptin levels and adipose tissue production of leptin. Design setting and subjects. Thirty-two men and 63 women with a large interindividual variation in body mass index (BMI), but otherwise healthy, were investigated after an overnight fast. Body fat (bioimpedance), abdominal subcutaneous adipose tissue secretion of leptin in vitro and serum leptin were determined. Results. Although there was no gender difference in mean BMI or fat cell size, mean percentage body fat was 49 in women and 36 in men (P , 0.001). At each level of BMI, serum leptin levels were about two times higher in women than in men (P , 0.001). Adipose tissue secretion rate of leptin in men was twothirds of that in women (P , 0.05). The gender differences in body fat content, serum leptin and leptin secretion were observed in obese (BMI . 27 kg m 22 ) as well as non-obese subjects. Serum leptin levels (P , 0.001) and leptin secretion rate (P , 0.01) correlated positively with body fat content in either sex. However, the gender differences in serum leptin (P , 0.001) and leptin secretion rate (P , 0.01) remained statistically significantly different even when the values were adjusted for body fat. Conclusion. The gender difference in circulating leptin concentrations can be due to at least two different mechanisms. A higher proportion of adipose tissue and increased production rate of leptin per unit mass of adipose tissue might explain why women have higher circulating leptin levels than men.
CD4+CD25high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4+CD25− responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-α, and IFN-γ secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.
Abstract. Hellström L, Large V, Reynisdottir S, Wahrenberg H, Arner P (Karolinska Institute at the MK-Division, Huddinge University Hospital, Stockholm, Sweden). The different effects of a Gln27Glu  2 -adrenoceptor gene polymorphism on obesity in males and in females. J Intern Med 1999; 245: 253-59. Objectives.To investigate the role of a polymorphism in codon 27 (Gln27Glu) of the  2 -adrenoceptor gene for obesity in males compared to previously investigated females with an association of this polymorphism to obesity. Design. Population-based study. Setting. Medical department at a University Hospital. Subjects. A total of 138 non-related Swedish males with body mass indexes (BMI) in the range 19.4-53.4 kg m Ϫ2 were recruited as: healthy volunteers, healthy obese subjects and subjects undergoing surgery for uncomplicated gallstone or abdominal hernia. In order to investigate the impact of gender, the results were compared with a subset of an earlier investigated female population of 109 Swedish females. Obesity was defined as a BMI Ͼ 27 kg m Ϫ2 . Main outcome measures.Genotype examination of  2 -adrenoceptor polymorphism in codon 27 with polymerase chain reaction and restriction fragment length polymorphism.Results. The allele frequency of Gln27 and Glu27 did not differ between males and females when obese and non-obese subjects were investigated together. However, in obese males, the frequency of the Glu27 allele was significantly decreased (P ϭ 0.034), whereas the frequency of this allele was increased in obese females (P ϭ 0.013). No impact of the female androgen status on the distribution of the Gln27Glu polymorphism could be demonstrated in the obese females. Conclusion.A positive association between obesity and the Glu27 genetic variant in the  2 -adrenoceptor exists in females, whereas in males there is a negative correlation between Glu27 and obesity. The findings suggest that different genetic factors contribute to obesity in males and females.
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